Heparanase activates the syndecan-syntenin-ALIX exosome pathway  

作　　者：Bart Roucourt Sofie Meeussen Jie Bao Pascale Zimmermann Guido David 

机构地区：[1]Laboratory for Glycobiology and Developmental Genetics, Department of Human Genetics, KU Leuven, Leuven, B-3000, Belgium [2]Laboratory for Signal Integration in Cell Fate Decision, Department of Human Genetics, KU Leuven, Leuven, B-3000, Belgium [3]Centre de Recherche en Cancerologie de Marseille (CRCM), Aix-Marseille UniversitY, Marseille, F-13284, France Inserm, U1068 [4]Institut Paoli-Calmettes CNRS, UMR7258, Marseille, F-13009, France

出　　处：《Cell Research》2015年第4期412-428,共17页细胞研究（英文版）

摘　　要：Exosomes are secreted vesicles of endosomal origin involved in signaling processes. We recently showed that the syndecan heparan sulfate proteoglycans control the biogenesis of exosomes through their interaction with synten- in-1 and the endosomai-sorting complex required for transport accessory component ALIX. Here we investigated the role of heparanase, the only mammalian enzyme able to cleave heparan sulfate internally, in the syndecan-synten- in-ALIX exosome biogenesis pathway. We show that heparanase stimulates the exosomal secretion of syntenin-1, syn- decan and certain other exosomal cargo, such as CD63, in a concentration-dependent manner. In contrast, exosomal CD9, CD81 and flotillin-1 are not affected. Conversely, reduction of endogenous heparanase reduces the secretion of syntenin-l-containing exosomes. The ability of heparanase to stimulate exosome production depends on syntenin-1 and ALIX. Syndecans, but not glypicans, support exosome biogenesis in heparanase-exposed cells. Finally, hepara- nase stimulates intraluminal budding of syndecan and syntenin-1 in endosomes, depending on the syntenin-ALIX in- teraction. Taken together, our findings identify heparanase as a modulator of the syndecan-syntenin-ALIX pathway, fostering endosomal membrane budding and the biogenesis of exosomes by trimming the heparan sulfate chains on syndecans. In addition, our data suggest that this mechanism controls the selection of specific cargo to exosomes.

关 键 词：heparan sulfate SYNDECAN HEPARANASE SYNTENIN exosome biogenesis exosomal cargo 

分 类 号：Q946.88[生物学—植物学] S852.659.6[农业科学—基础兽医学]